Role of histotripsy synergized CD40 signaling in the re-engineering of cold tumors

组织解剖协同 CD40 信号传导在冷肿瘤再造中的作用

• 批准号: 10390557
• 负责人: Ashish Ranjan
• 金额: $ 43.32万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390557
• 关键词: Abscopal effect; Adverse effects; Aftercare; Agonist; Anti-CD40; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biological Assay; CT26; CTLA4 gene; Cancer Patient; Canis familiaris; Cells; Clinical; Clinical Trials; Colonic Neoplasms; Data; Disease; Disease remission; Distant; Dose; Encapsulated; Engineering; Focused Ultrasound; Focused Ultrasound Therapy; Genes; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immunization; Immuno-Chemotherapy; Immunologic Tests; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Injections; Location; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Metastatic Melanoma; Modality; Modeling; Mus; Neoplasm Metastasis; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Polymers; Prostate; Proteins; Radiation therapy; Radio; Reagent; Regimen; Relapse; Resistance; Role; Signal Pathway; Signal Transduction; Skin Cancer; Solid; Solid Neoplasm; Sonication; Survival Rate; T-Lymphocyte; TNFRSF5 gene; Technology; Testing; Therapeutic; Tissues; Translating; Translations; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor Tissue; Tumor-infiltrating immune cells; base; cell motility; checkpoint therapy; clinically relevant; combinatorial; cytokine; cytotoxic; exhaust; experience; image guided; immune activation; immunogenic; immunogenicity; immunosuppressed; improved; improved outcome; in situ vaccination; innovation; lymphoid organ; melanoma; millisecond; novel; preservation; progenitor; programmed cell death ligand 1; programmed cell death protein 1; response; success; survival outcome; tumor; tumor microenvironment

Project Summary Advanced-stage metastatic melanoma is the deadliest form of skin cancer, typically resistant to chemo- and radiotherapy. For such patients, the advent of immune checkpoint inhibitors (ICIs) has been a revolutionary change, improving tumor remission and survival rates, reversing prior lack of progress. Although promising, a large proportion of patients, especially those with poorly immunogenic ("cold") tumors, show only modest response to ICIs, and even responders relapse frequently. New tumor-reengineering technologies are urgently needed to improve survival rates in patients with immunoresistant cold tumors. The objective of this project is to optimize an innovative combinatorial therapy based on local focused ultrasound-based histotripsy (HT) and anti- CD40 agonist antibody (aCD40) encapsulated polymeric microparticles (CMPs) to reprogram cold melanoma tumors. HT non-invasively and rapidly generates acellular antigen depots with sharp boundaries in solid cancers, while aCD40 activates antigen-presenting cells (APCs). Our murine melanoma studies found that CMP is more efficacious compared to soluble aCD40 alone, and when combined with ICI/HT achieves complete remission of untreated tumors. Based on this premise, we will test the central hypothesis that intratumorally-administered CMPs that serve the dual functions of tumor antigen capture and sustained CD40 activation with HT will achieve durable remission of locally-treated and remote untreated melanomas. To test our hypothesis, the aims are to 1) Determine efficacy of the HT and CMP combined regimen in murine tumor models varying in immunogenicity and burden, 2) Elucidate ICI resistance reversal mechanisms that drives abscopal effects with HT and CMP, and 3) translate our findings to clinical trials in dog veterinary patients with spontaneous malignant melanoma. Dog melanoma resembles human melanoma, and metastasizes aggressively, and is advantageous for assessing translatability of our combinatorial therapy. Transforming immunologically “cold” tumors to immunogenic ones in advanced stages of cancer is a challenging goal. The project results will enable rapid activation of cold melanomas by locally generating large tumor antigen depots that can synergize with CD40 signaling to improve efficacy against locally treated and distant untreated tumors. Our studies in clinically- relevant models will inform feasibility of improving survival in a large proportion of metastatic melanoma patients with immunotherapy-resistant tumors.

项目总结